American Journal of Medical Genetics 43:877-881 (1992)
Brief Clinical Report A Severe Case of Mandibuloacral Dysplasia in a Girl Constance Schrander-Stumpel,Ann Spaepen, Jean-Pierre Fryns, and Jan Dumon Department of Clinical Genetics, Academic Hospital Maastricht, University of Limburg, Maastrkht, the Netherlands (C.S.-S.); Centre for Human Genetics, University of Leuven (A.S.,J.P.F.), and Department of Medical Genetics, University of Antwerp (J.D.), Belgium We report on a 16-year-oldgirl with mandibuloacral dysplasia, a rare progeroid syndrome. She presented at age 2 years with thin skin on the limbs, characteristic face with prominent eyes, a pinched nose, microg nathia, and small mouth. Hair was sparse and brittle. The terminal phalanges were hypoplastic and showed acroosteolysis. On followup, hands and feet showed progressive camptodactyly of fingers and toes with total loss of subcutaneous tissue. The clavicles were hypoplastic.Intelligence was normal. We review the literature on the subject and discuss differential diagnosis. o 1992 Wiley-Liss, Inc.
KEY WORDS mandibular hypoplasia, clavicle hypoplasia, skin abnormality, acroosteolysis, hypoplastic distal phalanges, progeroid syndrome INTRODUCTION Mandibuloacral dysplasia (MAD), MIM number 248370, is a rare disorder originally described by Young et al. [19711.The syndrome is characterized by (postnatal) hypoplasia of the jaw and clavicles, short distal phalanges with acroosteolysis, distal skin atrophy, late closure of the cranial fontanelles and sutures, a thin, beaked nose and prominent eyes, and postnatal growth retardation. Cavalazzi et al. [1960] are supposed to have reported the first case [Gorlin et al., 19901. Their male patient was reported under the diagnosis of cleidocranial dysostosis (CCD).MAD is not a well-known progeroid syndrome and has been mistakenly diagnosed not only as CCD, but also as acrogeria [Levi et al., 19701 or as Werner syndrome [Cohen et al., 19731. Geograph-
Received for publication July 15,1991;revision received October 15, 1991. Address reprint requests to Dr. J.P. Fryns, Centre for Human Genetics, Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium.
0 1992 Wiley-Liss, Inc.
ically, most cases reported up to now originate from Italy [Tenconi et al., 19861. Here we report on a 16-year-old Belgian female patient with MAD.
CLINICAL REPORT The patient was born in 1974 to healthy, nonconsanguineous parents of Belgian origin. She is the 4th child and has 3 older sisters who are healthy. Paternal and maternal age at the time of her birth were both 35 years. She was born after an uneventful pregnancy of 34 weeks. Birthweight was 2,500 g. At birth, a small chin, small nose and mouth, and thin facial skin were present. She was hospitalized for many months because of serious feeding problems and respiratory difficulties originating from the small nose and mouth. She snored from the beginning. At one year, the weight was only 5 kg (5 kg below the 3rd centile). Despite the recurrent medical problems her motor milestones were only mildly delayed; she walked at 20 months. The mental development seemed normal. The skin posed great problems; at age 2 years, not only the skin on the face, especially around the nose, was very thin, but also on the limbs, the skin was so atrophic and tense that contractures and bad healing of small wounds occurred. At that time, the diagnosis of Hallermann-Streiff syndrome was suggested because of her characteristic facial appearance. She had a thin nose with hypoplastic nasal alae, prominent eyes, frontal bossing and thin, sparse hair; skin was very thin and the venous pattern was clearly visible underneath (Fig. 1). There was retrognathia and a small mouth. The anterior fontanel was still open; radiographs of the skull showed underdevelopment of the skull bones and multiple wormian bones (Fig. 2). The clavicles were hypoplastic. The terminal phalanges were short and the nails broad and dysplastic (Fig. 3). The joint mobility was reduced. Radiographs of the hands showed acroosteolysis of the distal phalanges (Fig. 4).The teeth were poorly implanted and the oral cavity was small. Many teeth had to be extracted. In childhood, she frequently had surgical treatment for small bony knots on both hands and toes. Because of recurrence, these knots were not treated subsequently. Their histological examination showed sclerotic tissue with calcification. At age 4 years, her somatic growth
878
Schrander-Stumpel et al.
Fig. 3. Hands of the girl at the age of 2 years. Thin skin overlying short terminal phalanges.
Fig. 1. Present girl at the age of2 years. Note the thin nose, prominent eyes, small mouth, thin skin with visible veins, and drooping shoulders.
cumference 49 cm (3rd centile); the shoulders were drooping. She spoke with a high nasal voice and wore spectacles for hypermetropia. There were scarce secondary sexual characteristics for she had been menstruatwas normal (length 25th centile, weight 50th centile and ing for about a year. The fair hair was scarce and brittle. head circumference 50th centile). A psychologic obser- The nose was thin and pointed, the eyes were prominent. vation at that time showed an I&of 100 on the Therman- The mouth was very small with limited ability to open; Merill intelligence scale. She has been attending regu- only few dental elements were present. The cheeks were lar schools on and off because of physical weakness. bulbous and the chin small. The skin of the face, skull, Repeated ophthalmologicexaminations were normal (no arms and legs was very thin with venous reticulum microphthalmia or cataracts). On re-examination at age clearly visible beneath. The skin on the trunk was 16 years, she was an intelligent, friendly girl (Fig. 5) thicker, with mottled hyperpigmentation. The skin alwith a height of 154 cm (between 3rd and 25th centile) ways felt moist. On palpation, the clavicles could not be and a weight of 34 kg (less than 3rd centile), head cir- felt. The hands were severely deformed since early childhood (Fig. 6). There was distal atrophy of the skin with contractures of the proximal and distal interphalangeal phalanges of all fingers. The distal phalanges were short, especially in finger 11. Multiple intracutaneous “warty” structures were visible on the hands; these nodules were bony on palpation and had clearly white spots in them, which the family said were identical to the ones removed in early childhood. On the plantar surface of the feet the same tumours were present, posing serious orthopedic problems. These nodules were also present in the skin of the external ears, the back of the head and the left iliac superior border. The feet were very thin with contractures of the toes and small terminal phalanges.
Fig. 2. X-ray of the skull at the age - of 2 years. Delaved ossification and multiple wormian bones.
DISCUSSION As far as we are aware, there are 20 described cases of MAD. Characteristic manifestations are progressive mandibular and clavicular hypoplasia, short distal phalanges with acroosteolysis, a thin, beaked nose, prominent eyes and delayed closure of the fontanelles and cranial sutures. The skin shows mottled hyperpigmentation on the trunk and distal atrophy. Alopecia or hypotrichosis and premature loss of the lower teeth can also
Mandibuloacral Dysplasia
879
Fig. 4. X-ray ofthe left hand the time ofbirth (A)and at the age of 2 years (B).Note the acroosteolysisof the distal phalanges of fingers I1 and V.
Fig. 5. A, Present girl at the age of 16 years. Note the scarce, abnormal hair, prominent eyes, thin, pinched nose, small mouth, bulbous cheeks and hanging shoulders. B,Profile of the girl at 16years. Small chin and prominent eyes.
occur. Intelligence is normal. The first symptoms appear between age one and 7 years and consist of shortening and thinning of the distal phalanges and receding of the chin. Later, the clavicles (partly) vanish [Gorlin et al., 1990; Zina et al., 19811.
The present girl fulfills the diagnostic criteria of MAD, and represents a severe expression of the syndrome. She presented at age 2 years with progressive thinning of the skin on the terminal phalanges and stiff joints, but was born with a thin facial skin and a small
880
Schrander-Stumpelet al.
Fig. 6 . A, B, Right hand at the age of 16 years. Extreme atrophia of the skin with contractures of the fingers; multiple bony nodules.
mouth and chin according to the parents. At age 2 years, the facial appearance of the patient was strikingly similar to that of a boy described by Danks et al. [19741. Moreover, both patients suffered from recurrent calcified nodules on the fingers and toes, which is not a frequent finding in the syndrome. A review of the clinical data in MAD is summarized in Table I. Table I contains 20 cases from 11families. Because of diagnostic confusion especially with the progeroid syndromes (acrogeria, Werner, HallermannStreiff), cleidocranial dysostosis (CCD), and pycnodysostosis, the number of cases in the literature may be underestimated. We included a case t h a t was diagnosed as Werner syndrome [Cohen et al., 19731, and one a s pycnodysostosis or CCD plus acroosteolysis [McKusick, 1966,19701. The boy reported by Cavalazzi et al. [19601 may represent a n intermediate between CCD and MAD since in this case skin features were not mentioned. McKusick's case was later described as pycnodysostosis L19721. The acrogeria of Gottron may pose differential diagnostic problems with MAD; in clinical reports described as acrogeria cases of MAD can be found-for instance, the boy described by Levi e t al. [1970]. One year later, Levi's case was correctly reported as MAD [Young e t al., 19711. In some cases of acrogeria, acroosteolysis of the terminal phalanges is reported [de Groot et al., 1980; Ho et al., 19871. These findings suggest nosologic overlap between acrogeria and MAD. The 3 brothers described by Mensing et al. [1982] as having a Werner-like syndrome, have normal growth, and no data are given about the terminal phalanges. They may represent mild cases of MAD [Gorlin et al., 19901, but in our opinion, these cases are
different from MAD, so we did not include them in Table I. The finding of manifestations characteristic of MAD in other known or unknown entities was well-documented in the patient described by Ramer and Ladda [1990].
The clinical manifestations in MAD can be progressive. This is clearly shown in some case reports with follow-up [Young et al., 1971; present study1 and is suggested in the family where the older of 2 sibs had more severe manifestations [Tenconi et al., 19861. However, variability in the familial cases exists: the older sib had less severe manifestations in sibship 2 described by Zina et al. [19811 and a similar expression was found in 3 sibships [Welsh, 1975; Palotta and Morgese, 1984; sibship 1, Zina et al., 19811. We found 8 isolated cases (7 males from the literature and the present girl) and 13 familial cases (7 females and 6 males). A comparison was made between the clinical data of the isolated cases and the clinical data of the familial patients. The familial cases were older a t the time of publication than the isolated: over 20 years and 3-14 years, respectively. In the familial cases, milder stigmata were seen, sometimes identified only after diagnosis of MAD in a sib [Zina et al., 19811. Inheritance undoubtedly is autosomal recessive; recurrences have been reported in male and female sibs. Consanguinity has never been documented but was suspected in 2 families [Zina et al., 1981; Tenconi et al., 19861. Two women have reproduced: they had normal children, although one of them had experienced 5 spontaneous abortions [Zina e t al., 1981; Welsh, 19751. In 3 boys, puberty was noted to be delayed [case 2, Young et al., 1971; Cohen et al., 1973; Palotta andMorgese, 19841.
Mandibuloacral Dysplasia
ACKNOWLEDGMENTS The authors thank Dr. R. Gorlin for suggesting the diagnosis of MAD in the present patient.
881
REFERENCES
Cavallazzi C, Cremoncini R, Quadri A (1960):Su di un caso di disostosi cleido-cranica. Riv Clin Paediatr 65312-326. Cohen LK, Thurmon TF, Salvaggio J (1973):Werner’s Syndrome. Cutis 12:76-80. Danks DM, Mayne V, Wettenhal HNB, Hall RK (1974): CraniomanTABLE I. Clinical Features in Mandibuloacral Dysplasia: dibular Dermatodysostosis. Birth Defects: OAS X (12):99--105. Summarized Overview Gorlin R, Pindborg J J , Cohen Jr (1990):Mandibuloacral dysplasia. In Gorlin RJ, Cohen MM, Levin SL (Eds.) “Syndromesofthe Head and Pos/informaab Neck,” 3rd Ed. New York: McGraw-Hill Book Company, pp 266Clinical data Present girl (n = 20) 267. 13:7 F Sex M:F de Groot WP, Tafelkruyer J, Woerdeman MJ (1980):Familial acrogeria Age at time of report (years 3, 5-60 16 (Gottron). Brit J Dermatol 103:213-223. Age of onset (years) 1,5-7 Birth Hall B, Mier R (1985): Mandibuloacral dysplasia: A rare progressive Postnatal growth retardation 15/18 disorder with postnatal onset. In Saul RA (Ed.) “Proceedings of the Intelligence Normal nl Greenwood Genetic Center.” Clinton SC: Jacobs Press, Inc, 4:125126. Stiff joints 14/14 Craniofacial Ho A, White SJ,Rasmussen J E (1987):Skeletal abnormalities of acroMandibular hypoplasia 19/20 geria, a progeroid syndrome. Skeletal Radio1 16:463-468. Thinbeaked nose 17119 Levi L, Bellani G, Vergani C, D’Alonzo R, Fiorelli G (1970):L’acrogeria Prominent eyes 17118 di Gottron. Descrizione di un caso. G Ital Dermatol 105:645-651. Alopecidthin hair 10/14 Mensing H, Schaeg G, Burck U, Meigel W (1982): Werner-SyndromDental anomalies 7/16 + artige Erkrankung bei drei Brudern. Beitrag zur DifferentialdiagPremature loss of lower teeth 7/12 nose der Voralte-rungessyndrome. Der Hautartz 33542-547. Cutaneous McKusick VA (1966): Medical Genetics. Pyknodysostosis. J Chron Dis Mottled hyperpigmentation 12/12 16:1188- 1189. Distal atrophy 18/18 McKusick VA (1972): “Heritable Disorders of Connective Tissue, 4th Nail abnormality 9/15 Ed.” St. Louis: CV Mosby, pp. 822-823. Skin biopsy performed’ 5x McKusick VA (1990): “Mendelian Inheritance in Man. 9th Ed.” BalSkeletal timore: John Hopkins University Press, p. 1304. Late closure of the cranial 515 Pallotta R, Morgese G (1984): Mandibuloacral dysplasia: A rare prosutures geroid syndrome. Two brothers confirm autosomal recessive inheriWormian bones 819 tance. Clin Genet 26:133-138. Clavicle hypoplasia 17/18 Ramer JC, Ladda RL (1990):Report of a male with features overlapping Short distal phalanges 18/19 geroderma osteodysplastica and mandibuloacral dysplasia. DysAcroosteolysis 15/17 morphol Clin Genet 4:66-78. Rib anomalies documented 7x ? Tenconi R, Miotti F, Audino G, Ferro R, Clementi M (1986): Another Vertebral anomalies 4x ? Italian Family With Mandibuloacral Dysplasia: Why Does it Seem documented More frequent in Italy? Am J Med Genet 24:357-364. Coxa valga described 3x Welsh 0 (1975): Study of a Family with a New Progeroid Syndrome. “Cavalazzi et al., 1960: Cohen et al., 1973; Danks et al., 1974: Hall and Birth Defects: OAS 11:25-38. Mier, 1985 and personal communication with Dr. B. Hall, 1991: Levi et Young LW, Radebaugh JF, Rubin Ph, Sensenbrenner JA, Fiorelli G al., 1970: McKusick, 1972: Palotta and Morgese, 1984; Tenconi et al., (1971):New syndrome manifested by mandibular hypoplasia, acro1986;Welsh, 1975;Young et al., 1971 (case 2 was reported by Levi et al., osteolysis, stiffjoints and cutaneous atrophia (mandibuloacral dys1970); Zina et al., 19811. plasia) in two unrelated boys. In Bergsma D (ed): “The Clinical delineation of Birth Defects, Orofacial Structures.” Baltimore: Willb A feature was noted to be positive when the report or clinical photoiams & Wilkins Co. for the National Foundation-March of Dimes, graphs were informative. BD:OAS VII (7): 291-297. ‘[Cohen et al., 1973: Welsh, 1975: Zina et al., 19811. Zina AM, Cravario A, Bundino S (1981): Familial mandibuloacral dysplasia. Br J Dermat 105:719-723.
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Brief Clinical Report A Severe Case of Mandibuloacral Dysplasia in a Girl Constance Schrander-Stumpel,Ann Spaepen, Jean-Pierre Fryns, and Jan Dumon Department of Clinical Genetics, Academic Hospital Maastricht, University of Limburg, Maastrkht, the Netherlands (C.S.-S.); Centre for Human Genetics, University of Leuven (A.S.,J.P.F.), and Department of Medical Genetics, University of Antwerp (J.D.), Belgium We report on a 16-year-oldgirl with mandibuloacral dysplasia, a rare progeroid syndrome. She presented at age 2 years with thin skin on the limbs, characteristic face with prominent eyes, a pinched nose, microg nathia, and small mouth. Hair was sparse and brittle. The terminal phalanges were hypoplastic and showed acroosteolysis. On followup, hands and feet showed progressive camptodactyly of fingers and toes with total loss of subcutaneous tissue. The clavicles were hypoplastic.Intelligence was normal. We review the literature on the subject and discuss differential diagnosis. o 1992 Wiley-Liss, Inc.
KEY WORDS mandibular hypoplasia, clavicle hypoplasia, skin abnormality, acroosteolysis, hypoplastic distal phalanges, progeroid syndrome INTRODUCTION Mandibuloacral dysplasia (MAD), MIM number 248370, is a rare disorder originally described by Young et al. [19711.The syndrome is characterized by (postnatal) hypoplasia of the jaw and clavicles, short distal phalanges with acroosteolysis, distal skin atrophy, late closure of the cranial fontanelles and sutures, a thin, beaked nose and prominent eyes, and postnatal growth retardation. Cavalazzi et al. [1960] are supposed to have reported the first case [Gorlin et al., 19901. Their male patient was reported under the diagnosis of cleidocranial dysostosis (CCD).MAD is not a well-known progeroid syndrome and has been mistakenly diagnosed not only as CCD, but also as acrogeria [Levi et al., 19701 or as Werner syndrome [Cohen et al., 19731. Geograph-
Received for publication July 15,1991;revision received October 15, 1991. Address reprint requests to Dr. J.P. Fryns, Centre for Human Genetics, Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium.
0 1992 Wiley-Liss, Inc.
ically, most cases reported up to now originate from Italy [Tenconi et al., 19861. Here we report on a 16-year-old Belgian female patient with MAD.
CLINICAL REPORT The patient was born in 1974 to healthy, nonconsanguineous parents of Belgian origin. She is the 4th child and has 3 older sisters who are healthy. Paternal and maternal age at the time of her birth were both 35 years. She was born after an uneventful pregnancy of 34 weeks. Birthweight was 2,500 g. At birth, a small chin, small nose and mouth, and thin facial skin were present. She was hospitalized for many months because of serious feeding problems and respiratory difficulties originating from the small nose and mouth. She snored from the beginning. At one year, the weight was only 5 kg (5 kg below the 3rd centile). Despite the recurrent medical problems her motor milestones were only mildly delayed; she walked at 20 months. The mental development seemed normal. The skin posed great problems; at age 2 years, not only the skin on the face, especially around the nose, was very thin, but also on the limbs, the skin was so atrophic and tense that contractures and bad healing of small wounds occurred. At that time, the diagnosis of Hallermann-Streiff syndrome was suggested because of her characteristic facial appearance. She had a thin nose with hypoplastic nasal alae, prominent eyes, frontal bossing and thin, sparse hair; skin was very thin and the venous pattern was clearly visible underneath (Fig. 1). There was retrognathia and a small mouth. The anterior fontanel was still open; radiographs of the skull showed underdevelopment of the skull bones and multiple wormian bones (Fig. 2). The clavicles were hypoplastic. The terminal phalanges were short and the nails broad and dysplastic (Fig. 3). The joint mobility was reduced. Radiographs of the hands showed acroosteolysis of the distal phalanges (Fig. 4).The teeth were poorly implanted and the oral cavity was small. Many teeth had to be extracted. In childhood, she frequently had surgical treatment for small bony knots on both hands and toes. Because of recurrence, these knots were not treated subsequently. Their histological examination showed sclerotic tissue with calcification. At age 4 years, her somatic growth
878
Schrander-Stumpel et al.
Fig. 3. Hands of the girl at the age of 2 years. Thin skin overlying short terminal phalanges.
Fig. 1. Present girl at the age of2 years. Note the thin nose, prominent eyes, small mouth, thin skin with visible veins, and drooping shoulders.
cumference 49 cm (3rd centile); the shoulders were drooping. She spoke with a high nasal voice and wore spectacles for hypermetropia. There were scarce secondary sexual characteristics for she had been menstruatwas normal (length 25th centile, weight 50th centile and ing for about a year. The fair hair was scarce and brittle. head circumference 50th centile). A psychologic obser- The nose was thin and pointed, the eyes were prominent. vation at that time showed an I&of 100 on the Therman- The mouth was very small with limited ability to open; Merill intelligence scale. She has been attending regu- only few dental elements were present. The cheeks were lar schools on and off because of physical weakness. bulbous and the chin small. The skin of the face, skull, Repeated ophthalmologicexaminations were normal (no arms and legs was very thin with venous reticulum microphthalmia or cataracts). On re-examination at age clearly visible beneath. The skin on the trunk was 16 years, she was an intelligent, friendly girl (Fig. 5) thicker, with mottled hyperpigmentation. The skin alwith a height of 154 cm (between 3rd and 25th centile) ways felt moist. On palpation, the clavicles could not be and a weight of 34 kg (less than 3rd centile), head cir- felt. The hands were severely deformed since early childhood (Fig. 6). There was distal atrophy of the skin with contractures of the proximal and distal interphalangeal phalanges of all fingers. The distal phalanges were short, especially in finger 11. Multiple intracutaneous “warty” structures were visible on the hands; these nodules were bony on palpation and had clearly white spots in them, which the family said were identical to the ones removed in early childhood. On the plantar surface of the feet the same tumours were present, posing serious orthopedic problems. These nodules were also present in the skin of the external ears, the back of the head and the left iliac superior border. The feet were very thin with contractures of the toes and small terminal phalanges.
Fig. 2. X-ray of the skull at the age - of 2 years. Delaved ossification and multiple wormian bones.
DISCUSSION As far as we are aware, there are 20 described cases of MAD. Characteristic manifestations are progressive mandibular and clavicular hypoplasia, short distal phalanges with acroosteolysis, a thin, beaked nose, prominent eyes and delayed closure of the fontanelles and cranial sutures. The skin shows mottled hyperpigmentation on the trunk and distal atrophy. Alopecia or hypotrichosis and premature loss of the lower teeth can also
Mandibuloacral Dysplasia
879
Fig. 4. X-ray ofthe left hand the time ofbirth (A)and at the age of 2 years (B).Note the acroosteolysisof the distal phalanges of fingers I1 and V.
Fig. 5. A, Present girl at the age of 16 years. Note the scarce, abnormal hair, prominent eyes, thin, pinched nose, small mouth, bulbous cheeks and hanging shoulders. B,Profile of the girl at 16years. Small chin and prominent eyes.
occur. Intelligence is normal. The first symptoms appear between age one and 7 years and consist of shortening and thinning of the distal phalanges and receding of the chin. Later, the clavicles (partly) vanish [Gorlin et al., 1990; Zina et al., 19811.
The present girl fulfills the diagnostic criteria of MAD, and represents a severe expression of the syndrome. She presented at age 2 years with progressive thinning of the skin on the terminal phalanges and stiff joints, but was born with a thin facial skin and a small
880
Schrander-Stumpelet al.
Fig. 6 . A, B, Right hand at the age of 16 years. Extreme atrophia of the skin with contractures of the fingers; multiple bony nodules.
mouth and chin according to the parents. At age 2 years, the facial appearance of the patient was strikingly similar to that of a boy described by Danks et al. [19741. Moreover, both patients suffered from recurrent calcified nodules on the fingers and toes, which is not a frequent finding in the syndrome. A review of the clinical data in MAD is summarized in Table I. Table I contains 20 cases from 11families. Because of diagnostic confusion especially with the progeroid syndromes (acrogeria, Werner, HallermannStreiff), cleidocranial dysostosis (CCD), and pycnodysostosis, the number of cases in the literature may be underestimated. We included a case t h a t was diagnosed as Werner syndrome [Cohen et al., 19731, and one a s pycnodysostosis or CCD plus acroosteolysis [McKusick, 1966,19701. The boy reported by Cavalazzi et al. [19601 may represent a n intermediate between CCD and MAD since in this case skin features were not mentioned. McKusick's case was later described as pycnodysostosis L19721. The acrogeria of Gottron may pose differential diagnostic problems with MAD; in clinical reports described as acrogeria cases of MAD can be found-for instance, the boy described by Levi e t al. [1970]. One year later, Levi's case was correctly reported as MAD [Young e t al., 19711. In some cases of acrogeria, acroosteolysis of the terminal phalanges is reported [de Groot et al., 1980; Ho et al., 19871. These findings suggest nosologic overlap between acrogeria and MAD. The 3 brothers described by Mensing et al. [1982] as having a Werner-like syndrome, have normal growth, and no data are given about the terminal phalanges. They may represent mild cases of MAD [Gorlin et al., 19901, but in our opinion, these cases are
different from MAD, so we did not include them in Table I. The finding of manifestations characteristic of MAD in other known or unknown entities was well-documented in the patient described by Ramer and Ladda [1990].
The clinical manifestations in MAD can be progressive. This is clearly shown in some case reports with follow-up [Young et al., 1971; present study1 and is suggested in the family where the older of 2 sibs had more severe manifestations [Tenconi et al., 19861. However, variability in the familial cases exists: the older sib had less severe manifestations in sibship 2 described by Zina et al. [19811 and a similar expression was found in 3 sibships [Welsh, 1975; Palotta and Morgese, 1984; sibship 1, Zina et al., 19811. We found 8 isolated cases (7 males from the literature and the present girl) and 13 familial cases (7 females and 6 males). A comparison was made between the clinical data of the isolated cases and the clinical data of the familial patients. The familial cases were older a t the time of publication than the isolated: over 20 years and 3-14 years, respectively. In the familial cases, milder stigmata were seen, sometimes identified only after diagnosis of MAD in a sib [Zina et al., 19811. Inheritance undoubtedly is autosomal recessive; recurrences have been reported in male and female sibs. Consanguinity has never been documented but was suspected in 2 families [Zina et al., 1981; Tenconi et al., 19861. Two women have reproduced: they had normal children, although one of them had experienced 5 spontaneous abortions [Zina e t al., 1981; Welsh, 19751. In 3 boys, puberty was noted to be delayed [case 2, Young et al., 1971; Cohen et al., 1973; Palotta andMorgese, 19841.
Mandibuloacral Dysplasia
ACKNOWLEDGMENTS The authors thank Dr. R. Gorlin for suggesting the diagnosis of MAD in the present patient.
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REFERENCES
Cavallazzi C, Cremoncini R, Quadri A (1960):Su di un caso di disostosi cleido-cranica. Riv Clin Paediatr 65312-326. Cohen LK, Thurmon TF, Salvaggio J (1973):Werner’s Syndrome. Cutis 12:76-80. Danks DM, Mayne V, Wettenhal HNB, Hall RK (1974): CraniomanTABLE I. Clinical Features in Mandibuloacral Dysplasia: dibular Dermatodysostosis. Birth Defects: OAS X (12):99--105. Summarized Overview Gorlin R, Pindborg J J , Cohen Jr (1990):Mandibuloacral dysplasia. In Gorlin RJ, Cohen MM, Levin SL (Eds.) “Syndromesofthe Head and Pos/informaab Neck,” 3rd Ed. New York: McGraw-Hill Book Company, pp 266Clinical data Present girl (n = 20) 267. 13:7 F Sex M:F de Groot WP, Tafelkruyer J, Woerdeman MJ (1980):Familial acrogeria Age at time of report (years 3, 5-60 16 (Gottron). Brit J Dermatol 103:213-223. Age of onset (years) 1,5-7 Birth Hall B, Mier R (1985): Mandibuloacral dysplasia: A rare progressive Postnatal growth retardation 15/18 disorder with postnatal onset. In Saul RA (Ed.) “Proceedings of the Intelligence Normal nl Greenwood Genetic Center.” Clinton SC: Jacobs Press, Inc, 4:125126. Stiff joints 14/14 Craniofacial Ho A, White SJ,Rasmussen J E (1987):Skeletal abnormalities of acroMandibular hypoplasia 19/20 geria, a progeroid syndrome. Skeletal Radio1 16:463-468. Thinbeaked nose 17119 Levi L, Bellani G, Vergani C, D’Alonzo R, Fiorelli G (1970):L’acrogeria Prominent eyes 17118 di Gottron. Descrizione di un caso. G Ital Dermatol 105:645-651. Alopecidthin hair 10/14 Mensing H, Schaeg G, Burck U, Meigel W (1982): Werner-SyndromDental anomalies 7/16 + artige Erkrankung bei drei Brudern. Beitrag zur DifferentialdiagPremature loss of lower teeth 7/12 nose der Voralte-rungessyndrome. Der Hautartz 33542-547. Cutaneous McKusick VA (1966): Medical Genetics. Pyknodysostosis. J Chron Dis Mottled hyperpigmentation 12/12 16:1188- 1189. Distal atrophy 18/18 McKusick VA (1972): “Heritable Disorders of Connective Tissue, 4th Nail abnormality 9/15 Ed.” St. Louis: CV Mosby, pp. 822-823. Skin biopsy performed’ 5x McKusick VA (1990): “Mendelian Inheritance in Man. 9th Ed.” BalSkeletal timore: John Hopkins University Press, p. 1304. Late closure of the cranial 515 Pallotta R, Morgese G (1984): Mandibuloacral dysplasia: A rare prosutures geroid syndrome. Two brothers confirm autosomal recessive inheriWormian bones 819 tance. Clin Genet 26:133-138. Clavicle hypoplasia 17/18 Ramer JC, Ladda RL (1990):Report of a male with features overlapping Short distal phalanges 18/19 geroderma osteodysplastica and mandibuloacral dysplasia. DysAcroosteolysis 15/17 morphol Clin Genet 4:66-78. Rib anomalies documented 7x ? Tenconi R, Miotti F, Audino G, Ferro R, Clementi M (1986): Another Vertebral anomalies 4x ? Italian Family With Mandibuloacral Dysplasia: Why Does it Seem documented More frequent in Italy? Am J Med Genet 24:357-364. Coxa valga described 3x Welsh 0 (1975): Study of a Family with a New Progeroid Syndrome. “Cavalazzi et al., 1960: Cohen et al., 1973; Danks et al., 1974: Hall and Birth Defects: OAS 11:25-38. Mier, 1985 and personal communication with Dr. B. Hall, 1991: Levi et Young LW, Radebaugh JF, Rubin Ph, Sensenbrenner JA, Fiorelli G al., 1970: McKusick, 1972: Palotta and Morgese, 1984; Tenconi et al., (1971):New syndrome manifested by mandibular hypoplasia, acro1986;Welsh, 1975;Young et al., 1971 (case 2 was reported by Levi et al., osteolysis, stiffjoints and cutaneous atrophia (mandibuloacral dys1970); Zina et al., 19811. plasia) in two unrelated boys. In Bergsma D (ed): “The Clinical delineation of Birth Defects, Orofacial Structures.” Baltimore: Willb A feature was noted to be positive when the report or clinical photoiams & Wilkins Co. for the National Foundation-March of Dimes, graphs were informative. BD:OAS VII (7): 291-297. ‘[Cohen et al., 1973: Welsh, 1975: Zina et al., 19811. Zina AM, Cravario A, Bundino S (1981): Familial mandibuloacral dysplasia. Br J Dermat 105:719-723.
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